OCENA EFEKTIVNIH DOZ RADONA, KI TEMELJIJO NA RAZLIČNIH MERILNIH TEHNIKAH

In my master\u27s thesis, I have focused on radon gas in 43 buildings used for different purposes (23 schools, 3 kindergartens, 16 offices and a residential house) in which preliminary measurements had shown higher concentrations of radon gas. I carried out measurements of radon and short-lived radon products whilst simultaneously employing different measurement techniques. In all 43 buildings, I measured the instantaneous concentration of radon by using scintillation cellsin 18 buildings, I additionally measured the average concentration of radon by using solid state nuclear track detectors and in 10 buildings, I measured concentration retrospectively with solid state nuclear track detectors. In four selected buildings (a school, a kindergarten, an office and a residential house), I carried out the measurements by using all of the available equipment. I monitored the daily fluctuations of concentration of radon and short-lived radon products by using continuous monitors in 14 buildings. This is how I obtained the factor of radioactive equilibrium between radon and its short-lived products. Based on the results obtained, I calculated the effective doses. As the basis for calculating the doses, I used the instantaneous and average concentrations of radon and the equilibrium factor taken from literature (0.40) or own measurements. I compared the doses and critically evaluated them. In contrast to the previous research, I researched radon exclusively in areas with increased risk for radon. I studied the influence of the working regime on the concentration of radon in different working environments (i.e. a school, a kindergarten and an office).V svoji magistrski nalogi sem se osredotočila na radon v 43 zgradbah različne namembnosti (23 šol, 3 vrtci, 16 pisarn in stanovanjska hiša), kjer so predhodne meritve pokazale povišane koncentracije. Izvedla sem meritve radona in radonovih kratkoživih produktov in pri tem sočasno uporabila različne merilne tehnike. V vseh 43 zgradbah sem izmerila trenutno koncentracijo radona s scintilacijskimi celicami, v 18 zgradbah dodatno tudi povprečno koncentracijo z detektorji jedrskih sledi in v 10 zgradbah retrospektivno koncentracijo z detektorji jedrskih sledi. V štirih izbranih zgradbah (šola, vrtec, pisarna, stanovanjska hiša) sem izvedla meritve z vso razpoložljivo opremo. Dnevno spreminjanje koncentracije radona in radonovih kratkoživih produktov sem spremljala s kontinuirnimi merilniki v 14 zgradbah in tako dobila faktor radioaktivnega ravnotežja (ravnotežni faktor) med radonovimi kratkoživimi produkti in radonom. Na osnovi dobljenih rezultatov sem ocenila efektivne doze. Kot osnovo za izračun doz sem uporabila izmerjene trenutne in povprečne koncentracije radona ter ravnotežni faktor iz literature (0.40) ali meritev. Doze sem primerjala med seboj in jih kritično ocenila. Za razliko od dosedanjih raziskav, sem radon preiskovala izključno na področjih s povečanim tveganjem. Študirala sem vpliv delovnega režima na koncentracijo radona v različnih delovnih okoljih (šola, vrtec, pisarna)

EFFECT OF TUMOR NECROSIS FACTOR ALPHA INHIBITORS ON DENDRITIC CELLS IN INTESTINAL MUCOSA OF PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Prebavni trakt je stalno v stiku s številnimi antigeni, zato mora imunski sistem prepoznati in odstraniti škodljive mikrobe ter hkrati razviti imunsko toleranco proti neškodljivim mikrobom. Velik pomen pri regulaciji imunskega odziva imajo dendritične celice. Motnja v regulaciji imunskega odziva pri genetsko predisponirani osebi lahko vodi v razvoj kronične vnetne črevesne bolezni. V doktorski nalogi smo skušali razjasniti vpliv zaviralcev tumor nekroznega faktorja alfa (TNF&#945) na dendritične celice (DC) bolnikov s kronično vnetno črevesno boleznijo ter opredeliti njihovo vlogo pri odzivu na tovrstno zdravljenje. Želeli smo poiskati napovedne dejavnike s pomočjo katerih bi lahko napovedali odziv na takšno zdravljenje. V raziskavo smo vključili trideset bolnikov s kronično vnetno črevesno boleznijo (14 z ulceroznim kolitisom in 16 s Crohnovo boleznijo). Vsem bolnikom smo odvzeli bioptične vzorce sluznice debelega črevesa pred zdravljenjem z zaviralci TNF&#945(infliksimab pri trinajstih bolnikih ter adalimumab pri sedemnajstih bolnikih) in po njem. S pretočno citometrijo smo v odvzetih vzorcih črevesne sluznice opredelili fenotip in delež konvencionalnih in plazmacitoidnih dendritičnih celic. Aktivnost bolezni pred začetkom zdravljenja in po njem smo ocenjevali endoskopsko. Pred začetkom zdravljenja je bil delež konvencionalnih dendritičnih celic v vneti sluznici višji (7,8 %) kot v nevneti (4,5 %p = 0,003), medtem ko je bil delež dendritičnih celic, ki so izražale CD103+, v vneti sluznici nižji (47,1 %) kot v nevneti (57,3 %p = 0,03). Po 12 tednih zdravljenja je delež konvencionalnih dendritičnih celic v vneti sluznici upadel s 7,8 % na 4,5 % (p = 0,014), delež dendritičnih celic CD103+ je ostal nespremenjen. 18 bolnikov (60 %) se je odzvalo na zdravljenje z zaviralci TNF&#945. V vneti sluznici teh bolnikov je bil delež konvencionalnih dendritičnih celic pred zdravljenjem pomembno višji kot pri neodzivnih bolnikih (9,16 % proti 4,4 %p < 0,01). Pri teh bolnikih je bila tudi višja izraženost HLA-DR na površini DC (MFI 12152 proti 8837p = 0,038). Določanje deleža konvencionalnih dendritičnih celic v vneti sluznici bolnikov s kronično vnetno črevesno boleznijo pred začetkom zdravljenja bi lahko uporabili kot napovednik odziva na zdravljenje z zaviralci TNF&#945. 93 % bolnikov z deležem konvencionalnih dendritičnih celic nad 7 % se je namreč odzvalo na zdravljenje.Inappropriate immune response to gut microbiota is involved in the pathogenesis of inflammatory bowel disease. Dendritic cells play a crucial role in the control of inflammation and immune tolerance in the gut. We aimed to investigate the effects of tumor necrosis factor alpha (TNF&#945) inhibitors on intestinal dendritic cells of patients with inflammatory bowel disease and their potential role in predicting response to treatment. Also, we wished to find the predictors of response on such treatment. Intestinal biopsies (inflamed and uninflamed areas) were obtained from 30 patients with inflammatory bowel disease (14 ulcerative colitis patients and 16 Crohn\u27s disease patients) before and after the treatment with TNF&#945inhibitors (infliximab 13 patients, adalimumab 17 patients). The proportions of lamina propria dendritic cells phenotypes were analyzed using flow cytometry. Disease activity was endoscopically assessed at baseline and after induction treatment. At baseline, the proportion of conventional dendritic cells was higher in inflamed (7,8%) compared to uninflamed mucosa (4,5%) (p = 0.003) and the proportion of CD103+ dendritic cells was lower in inflamed (47,1%) versus uninflamed mucosa (57,3%) (p = 0.03). After 12 weeks of treatment, the proportion of conventional dendritic cells in inflamed mucosa decreased from 7,8% to 4,5% (p = 0.014), whereas the proportion of CD103+ dendritic cells remained unchanged. 18 out of 30 (60%) patients responded to treatment at week 12. Responders had significantly higher proportion of conventional dendritic cells (9,16% vs 4,4%, p < 0.01) with higher expression of HLA-DR (MFI 12152 vs 8837, p = 0.038) in inflamed mucosa before treatment compared to non-responders. The proportion of conventional dendritic cells above 7% in inflamed inflammatory bowel disease mucosa before treatment predicts endoscopic response to TNF&#945inhibitors. 93% of patients with proportion of conventional dendritic cells above 7% responded to treatment

Remission Is Maintained after Switch from Dose-Optimised Intravenous Treatment to Subcutaneous Treatment with Vedolizumab in Inflammatory Bowel Disease

Background and Objectives: The subcutaneous (SC) formulation of vedolizumab has proven to be effective for the maintenance of remission after intravenous induction. Little is known about the efficacy of switching from intravenous maintenance treatment to SC. We aimed to assess the real-world efficacy of switching to SC treatment and to assess the impact of a baseline treatment regimen. Materials and Methods: In this observational cohort study, adult patients with inflammatory bowel disease who were switched to SC vedolizumab maintenance treatment were enrolled. Patients after intravenous induction and patients who switched from intravenous maintenance treatment (every 8 weeks or every 4 weeks) were included. The SC vedolizumab dosing was 108 mg every 2 weeks, regardless of the previous regimen. The clinical, biochemical, and endoscopic disease activity parameters and vedolizumab serum concentrations at the time of the switch and at the follow-up were assessed. Results: In total, 135 patients (38% Crohn’s disease, 62% ulcerative colitis) were switched to SC vedolizumab treatment. The median time to the first follow-up (FU) was 14.5 weeks (IQR 12–26), and the median time to the second FU was 40 weeks (IQR 36–52). Nine patients (7%) discontinued SC vedolizumab treatment, with two-thirds of them discontinuing due to active disease. In all dosing regimens, there were no significant changes in the clinical scores and CRP at the baseline and first and second FUs. Clinical and biochemical remission appeared to be maintained irrespective of the previous dosing regimen. Conclusions: The results of this real-world study suggest that the maintenance of clinical and biomarker remission can be achieved in patients who switched from intravenous to SC vedolizumab. The baseline vedolizumab dosing regimen (every 4 weeks versus every 8 weeks) did not have an impact on outcomes

Insights into treatment of complex Crohn's perianal fistulas

Complex perianal fistula is a common complication of Crohn's disease (CD) which leads to negative impact on patient's quality of life. Successful management of the disease requires a multidisciplinary approach, including a gastroenterologist and a colorectal surgeon, applying combined surgical and medical therapy. One of frequently practiced surgical procedures is seton placement in the fistula tract, which is used to control perianal sepsis and drain the fistula, while preventing recurrent abscess formation.Darvadstrocel, a suspension of expanded, allogeneic, adipose-derived, mesenchymal stem cells, is safe and effective for treatment-refractory complex perianal fistulas in patients with Crohn's disease. Following approval of darvadstrocel, the INSPIRE registry is being conducted in order to evaluate long-term safety and effectiveness of the drug on a large, heterogenous population.An online expert meeting was held from March 20 to March 30, 2023, which provided relevant insights into the decision-making process regarding seton use and obtained feedback on the first experiences with darvadstrocel. The aim of this article is to present the perspectives from gastroenterologists and colorectal surgeons practicing in Czechia, Hungary, Israel, Lithuania, Serbia, and Slovenia in topics such as diagnosis and treatment options for patients with complex Crohn's perianal fistulas (CPF), specifically focusing on the use of setons and darvadstrocel.During this virtual session, unavailability of comprehensive data on safety and efficacy of available treatment procedures was emphasized as an important obstacle towards development of standardized recommendations and improvement of outcomes in treatment of (CPF). Furthermore, achieving consensus in seton use, duration of its placement, and frequency of change is recognized as one of CPF treatments major challenges. Despite these issues, it is important to promote better understanding and treatment of complex perianal fistulas in order to improve the quality of life of those affected by this condition

Peak Concentrations of Ustekinumab After Intravenous Induction Therapy Identify Patients With Crohn's Disease Likely to Achieve Endoscopic and Biochemical Remission.

BACKGROUND & AIMS: Little is known about the relationship between ustekinumab exposure during the first 2 weeks of treatment and outcomes of patients with Crohn's disease (CD). We investigated the relationship between serum concentrations of ustekinumab during the first 2 weeks of treatment and endoscopic and biochemical remission in patients with CD. METHODS: In a prospective observational study, we measured concentrations of ustekinumab in serum samples from 41 consecutive patients who started treatment with ustekinumab (approximately 6 mg/kg, intravenously, then 90 mg every 8 weeks), due to endoscopic markers of active CD, at a single center from October 2017 through January 2019. We measured ustekinumab exposure parameters during the first 2 weeks (peak concentration measured immediately after intravenous infusion, week 2 concentration, and area under the curve through week 2). We investigated the correlation between these parameters and endoscopic remission (simple endoscopic score for CD scores of 3 or less without ulceration, assessed centrally) and biochemical remission (level of fecal calprotectin below 100 mg/kg) using the Mann-Whitney U test. RESULTS: Endoscopic remission was achieved in 10 patients (24.4%) at week 24; biochemical remission was achieved in 17 patients (41.5%) at week 8, 17 patients (41.5%) at week 16, and 21 patients (51.2%) at week 24. Peak concentrations associated with endoscopic remission (area under the receiver operating characteristic curve, 0.717; 95% CI, 0.517-0.916); 6 of 13 patients (46%) with peak concentrations above 105 μg/mL (upper tercile) achieved endoscopic remission, compared with only 1 of 14 patients (7%) with peak concentrations below 88 μg/mL (lower tercile). All exposure parameters during the first 2 weeks were associated with biochemical remission. There was no significant difference between the associations of peak concentrations, week-2 concentrations, area under the curve through week 2, or later exposure measures (at weeks 4 and 8) with biochemical or endoscopic remission. CONCLUSIONS: In a prospective study, we found that serum concentrations of ustekinumab as early as 1 hour after intravenous infusion might be used to identify patients with CD most likely to achieve endoscopic remission. This early measurement might be used to optimize treatment of CD.status: Published onlin

Slovenska priporočila za obravnavo odraslih bolnikov s kronično odpovedjo prebavil

no abstractSlovenska priporočila za obravnavo bolnikov z kronično odpovedjo prebavil so povzeta so po smernicah Evropskega združenja za klinično prehrano in metabolizem (angl. ESPEN; European Society for Clinical Nutrition and Metabolism) in prilagojena slovenskim izkušnjah zdravljenja odpovedi prebavil. Pretežni del bolnikov z odpovedjo prebavil predstavljajo bolniki s sindromom kratkega črevesa (SKČ), zato je poudarek priporočil na diagnostiki, obravnavi in zdravljenju bolnikov s SKČ. Namen priporočil je vzpostavitev bolj učinkovite prepoznave in obravnave bolnikov z odpovedjo ter vzpostavitvi temeljnih strokovnih izhodišč za zdravljenje teh bolnikov v Sloveniji. Dejavnost zdravljenja kronične odpovedi prebavil z parenteralno prehrano na domu pri odrasli pacientih je bila v Sloveniji formalno vzpostavljena leta 2008, v 13 letih smo zdravili več kot 230 pacientov, v začetku leta 2021 je v 2 centrih (OI Ljubljana, UKC Ljubljana) v zdravljenje vključeno 95 odraslih bolnikov. Pred 6 leti Smo paciente v programu zdravljenja odpovedi prebavil v okviru OI LjubljanA vključili v evropski register premljanja bolnikov na Parenteralni prehrani na domu (PPD), v okviru ESPEN

Genska terapija v onkologiji, prvi razvojni koraki v Sloveniji

Gene therapy is also attracting interest in oncology. Probably the most interesting approach is immunostimulation. Plasmid DNA can be constructed, which is coding for a specific immunostimulatory molecule, which is then delivered into the cells, either in tumour or normal tissue. The transfected tissue then becomes the producer of the molecules encoded in the plasmid. The product is then released from the cells, either locally or systemically into the bloodstream. Since plasmids have hampered transport through the plasma membrane, delivery systems are needed that are either viral or nonviral. In our studies we predominantly use the non-viral transfection system, based on electroporation of the cells.Interleukin 12 (IL-12) is a cytokine with well-known anti-tumour and anti-angiogenic function. Therefore, in the SmartGene.si project we wanted to construct a plasmid DNA which is coding for IL-12 (plasmid phIL12), and perform all the necessary testing and prepare the documentation for its clinical testing in the treatment of skin tumours. The SmartGene.si consortium comprises partners from academia and industry. In the project it was necessary to prepare the plasmid according to the European Medicinal Agency (EMA) recommendations. For the application for the study approval submitted to the Agency for Medical Products and Medical Devices of the Republic of Slovenia (JAZMP), it was necessary to perform pharmacological, pharmacokinetic, and efficiency testing of phIL12. Thereafter, we had to develop the process and the facility, and prepare the drug.During the last three years, we have achieved all the goals and obtained the approval of the JAZMP for clinical testing of the product phIL12 in humans. We also obtained the approval of the National Ethics Committee. Currently, we are testing phIL-12 in a Phase I clinical protocol on head and neck skin tumours, with the aim to test the safety and feasibility of intratumoral gene electrotransfer of the plasmid phIL12. Another goal of the study is to determine a suitable dose of plasmid that could be used in future studies as adjuvant treatment to ablative therapies such as radiotherapy or electrochemotherapy.Genska terapija postaja čedalje bolj zanimiva tudi v onkologiji. Med aplikacijami je morda najzanimivejša imunostimulacija. Pripravimo lahko plazmidno DNA, ki nosi zapis za različne imunostimulatorne molekule, ki jih vnesemo v celice tumorjev ali normalnih tkiv. Ta tkiva postanejo proizvajalci teh molekul, ki lahko delujejo lokalno ali pa se izločajo tudi sistemsko v krvni obtok. Ker plazmidna DNA ne prehaja celične membrane, so potrebni dostavni sistemi, virusni ali nevirusni. V naših študijah uporabljamo predvsem nevirusni dostavni sistem – elektroporacijo.Interlevkin 12 (IL-12) je eden od zanimivih citokinov, za katerega je znano protitumorsko delovanje s spodbujanjem imunskega odziva in antiangiogenim delovanjem. Namen projekta SmartGene.si je bil pripraviti plazmid z zapisom za interlevkin 12 (plazmid phIL12) in pripraviti vse potrebno za njegovo klinično testiranje za zdravljenje kožnih tumorjev. V konzorciju smo združili moči s partnerji z akademskega in industrijskega področja. Treba je bilo pripraviti plazmid za uporabo v humani onkologiji po zahtevah Evropske agencije za zdravila (EMA). Za prijavo klinične študije na Javno agencijo za zdravila in medicinske pripomočke (JAZMP) smo morali izvesti tudi vse neklinične raziskave o varnosti in učinkovitosti zdravila. Nato je bilo treba razviti postopek priprave zdravila, zagotoviti primerne prostore za pripravo in izvedbo postopka priprave zdravila.V treh letih smo dosegli vse te zastavljene cilje in dobili dovoljenje za izvajanje klinične študije na kožnih tumorjih, ki ga je izdala JAZMP na osnovi pozitivnega mnenja Komisije Republike Slovenije za medicinsko etiko. Zdaj poteka klinična študija faze I preizkušanja plazmida phIL12 na kožnih tumorjih glave in vratu z namenom preveriti varnost in sprejemljivost genskega elektroprenosa plazmida v tumorje. Cilj študije je prav tako določiti primeren odmerek zdravila, ki bi ga v nadaljnji klinični študiji uporabili kot adjuvantno zdravljenje k ablativnim terapijam, kot sta radioterapija ali elektrokemoterapija

Gene therapy in oncology, first steps of development in Slovenia

Genska terapija postaja čedalje bolj zanimiva tudi v onkologiji. Med aplikacijami je morda najzanimivejša imunostimulacija. Pripravimo lahko plazmidno DNA, ki nosi zapis za različne imunostimulatorne molekule, ki jih vnesemo v celice tumorjev ali normalnih tkiv. Ta tkiva postanejo proizvajalci teh molekul, ki lahko delujejo lokalno ali pa se izločajo tudi sistemsko v krvni obtok. Ker plazmidna DNA ne prehaja celične membrane, so potrebni dostavni sistemi, virusni ali nevirusni. V naših študijah uporabljamo predvsem nevirusni dostavni sistem – elektroporacijo. Interlevkin 12 (IL-12) je eden od zanimivih citokinov, za katerega je znano protitumorsko delovanje s spodbujanjem imunskega odziva in antiangiogenim delovanjem. Namen projekta SmartGene.si je bil pripraviti plazmid z zapisom za interlevkin 12 (plazmid phIL12) in pripraviti vse potrebno za njegovo klinično testiranje za zdravljenje kožnih tumorjev. V konzorciju smo združili moči s partnerji z akademskega in industrijskega področja. Treba je bilo pripraviti plazmid za uporabo v humani onkologiji po zahtevah Evropske agencije za zdravila (EMA). Za prijavo klinične študije na Javno agencijo za zdravila in medicinske pripomočke (JAZMP) smo morali izvesti tudi vse neklinične raziskave o varnosti in učinkovitosti zdravila. Nato je bilo treba razviti postopek priprave zdravila, zagotoviti primerne prostore za pripravo in izvedbo postopka priprave zdravila. V treh letih smo dosegli vse te zastavljene cilje in dobili dovoljenje za izvajanje klinične študije na kožnih tumorjih, ki ga je izdala JAZMP na osnovi pozitivnega mnenja Komisije Republike Slovenije za medicinsko etiko. Zdaj poteka klinična študija faze I preizkušanja plazmida phIL12 na kožnih tumorjih glave in vratu z namenom preveriti varnost in sprejemljivost genskega elektroprenosa plazmida v tumorje. Cilj študije je prav tako določiti primeren odmerek zdravila, ki bi ga v nadaljnji klinični študiji uporabili kot adjuvantno zdravljenje k ablativnim terapijam, kot sta radioterapija ali elektrokemoterapija.Gene therapy is also attracting interest in oncology. Probably the most interesting approach is immunostimulation. Plasmid DNA can be constructed, which is coding for a specific immunostimulatory molecule, which is then delivered into the cells, either in tumour or normal tissue. The transfected tissue then becomes the producer of the molecules encoded in the plasmid. The product is then released from the cells, either locally or systemically into the bloodstream. Since plasmids have hampered transport through the plasma membrane, delivery systems are needed that are either viral or nonviral. In our studies we predominantly use the non-viral transfection system, based on electroporation of the cells. Interleukin 12 (IL-12) is a cytokine with well-known anti-tumour and anti-angiogenic function. Therefore, in the SmartGene.si project we wanted to construct a plasmid DNA which is coding for IL-12 (plasmid phIL12), and perform all the necessary testing and prepare the documentation for its clinical testing in the treatment of skin tumours. The SmartGene.si consortium comprises partners from academia and industry. In the project it was necessary to prepare the plasmid according to the European Medicinal Agency (EMA) recommendations. For the application for the study approval submitted to the Agency for Medical Products and Medical Devices of the Republic of Slovenia (JAZMP), it was necessary to perform pharmacological, pharmacokinetic, and efficiency testing of phIL12. Thereafter, we had to develop the process and the facility, and prepare the drug. During the last three years, we have achieved all the goals and obtained the approval of the JAZMP for clinical testing of the product phIL12 in humans. We also obtained the approval of the National Ethics Committee. Currently, we are testing phIL-12 in a Phase I clinical protocol on head and neck skin tumours, with the aim to test the safety and feasibility of intratumoral gene electrotransfer of the plasmid phIL12. Another goal of the study is to determine a suitable dose of plasmid that could be used in future studies as adjuvant treatment to ablative therapies such as radiotherapy or electrochemotherapy

6th International Conference The Future of Information Sciences INFuture2017: Integrating ICT in Society

This is the sixth publication in the series of biennial international conferences, The Future of Information Sciences (INFuture) organised by the Department of Information and Communication Sciences, Faculty of Humanities and Social Sciences, University of Zagreb. This year it is co-organised with the Miroslav Krleža Institute of Lexicography. The title of the conference is INFuture2017: Integrating ICT in Society. The conference explores the influence the information and communication sciences have on the society as a whole.This is the sixth publication in the series of biennial international conferences, The Future of Information Sciences (INFuture) organised by the Department of Information and Communication Sciences, Faculty of Humanities and Social Sciences, University of Zagreb. This year it is co-organised with the Miroslav Krleža Institute of Lexicography. The title of the conference is INFuture2017: Integrating ICT in Society. The conference explores the influence the information and communication sciences have on the society as a whole

6th International Conference The Future of Information Sciences INFuture2017: Integrating ICT in Society

This is the sixth publication in the series of biennial international conferences, The Future of Information Sciences (INFuture) organised by the Department of Information and Communication Sciences, Faculty of Humanities and Social Sciences, University of Zagreb. This year it is co-organised with the Miroslav Krleža Institute of Lexicography. The title of the conference is INFuture2017: Integrating ICT in Society. The conference explores the influence the information and communication sciences have on the society as a whole.This is the sixth publication in the series of biennial international conferences, The Future of Information Sciences (INFuture) organised by the Department of Information and Communication Sciences, Faculty of Humanities and Social Sciences, University of Zagreb. This year it is co-organised with the Miroslav Krleža Institute of Lexicography. The title of the conference is INFuture2017: Integrating ICT in Society. The conference explores the influence the information and communication sciences have on the society as a whole